Intrapatient Coefficient Of Variation Research Articles

P966 The intra-patient variability of adalimumab clearance during an intensive sampling study of Crohn’s disease patients receiving maintenance therapy

Abstract Background Lower adalimumab (ADA) clearance (CL) is associated with improved outcomes in Crohn’s disease (CD) and may be a superior pharmacokinetic (PK) measure than ADA concentrations. We compared intra-patient variability in ADA CL and concentrations within a 14-day treatment cycle and across two consecutive cycles under maintenance treatment. Methods In a previous PK study of CD patients receiving maintenance ADA 40mg fortnightly, samples were collected intensively at 3 visits (day 4-6, 7-9, and 13-14 post dose) across 2 consecutive cycles. Available sera from this cohort were subsequently used to measure ADA concentrations (lower limit quantification: <1.6 µg/mL) and antibody to adalimumab (ATA) status using a drug tolerant homogeneous mobility shift assay, and albumin. Apparent ADA CL (L/day) was calculated incorporating these measure parameters in a nonlinear mixed effect model with Bayesian priors (under steady state assumption) with dose and inter-dose interval with ATA and albumin as covariate. Rates of sustained clinical and biochemical remission (Harvey Bradshaw Index (HBI) score consistently <5 and CRP levels consistently <3 mg/L) were estimated for each patient. Longitudinal changes in PK parameters within-and-across cycles were evaluated using intra-patient coefficient of variation and linear mixed effect models. Results Sera was available from 70 study visits in 12 patients (6 males, mean age 36 years). Median ADA concentrations and CL were 8 µg/mL (IQR 6.0-10.4) and 0.374 L/day (IQR 0.29-0.43), respectively, with ATA detected in one patient (#9). Estimated ADA concentrations and CL is presented in the Table. Intra-patient variability in CL was much lower across the two 14-day cycle (9% and 7%, respectively) compared to intra-patient variability in ADA concentration (15% and 13%, respectively). Linear mixed effect models confirmed these findings with no impact of sampling time on CL (intercept=0.46±0.12 L/day; slope estimate=0.002±0.002 L/day; p=0.16) as compared to significant change in ADA concentrations (intercept=10.6±1.2 µg/mL; slope estimate=-0.25±0.03 µg/mL; p<0.01) over inter-dose interval sampling time. Sustained clinical and biochemical remission was achieved in 5/12 patients (42%); none presented with CL >0.8 L/day (a cut-off previously associated with worse outcomes). Of 7 patients without sustained clinical and biochemical remission, two presented with optimal concentrations (> 10 µg/mL), thus suggestive of mechanistic failure, and one developed ATA, lower concentration and higher ADA CL. Conclusion CL is subject to less intra-patient variability than ADA concentrations, supporting its assessment at any time point within a 14-day treatment cycle.

Therapeutic drug monitoring of corticosteroids/β2-agonists in the hair of patients with asthma: an open-label feasibility study.

Background: Although adherence to inhaled medication is critically important for treatment efficiency, around half of patients taking these drugs are non-adherent or make critical errors when using their delivery device. Segmental hair analysis might be a valuable tool for therapeutic monitoring because hair concentrations reflect exposure from month to month. The objective of the present proof-of-concept study was to establish the feasibility of segmental hair analysis of inhaled budesonide and formoterol in asthma patients. Methods: We conducted a prospective, open-label, interventional study of adult patients being treated with budesonide/formoterol for controlled, moderate-to-severe asthma (CorticHair, NCT03691961). Asthma control, lung function, and medication adherence were recorded. Hair samples were taken 4 months after enrolment and cut into four 1cm segments. Results: Samples were available from 21 patients (20 women; median age: 53; median budesonide dose: 600μg/d). Budesonide and formoterol were detected in samples from 18 to 13 patients, respectively. The median hair concentrations were 6.25pg/mg for budesonide and 0.9pg/mg for formoterol. The intrapatient coefficient of variation between hair segments was 21% for budesonide and 40% for formoterol. Pearson's coefficients for the correlations between the hair concentration and the self-reported drug dose and the prescribed drug dose were respectively 0.42 (p = 0.08) and 0.29 (p = 0.25) for budesonide and 0.24 (p = 0.44) and 0.17 (p = 0.57) for formoterol. Conclusion: Segmental hair analysis of inhaled medications was feasible, with low intrapatient variability. This innovative, non-invasive means of assessing monthly drug exposure might help physicians to personalize drug regimens for patients with difficult-to-treat asthma.

Therapeutic drug monitoring of fenfluramine in clinical practice: Pharmacokinetic variability and impact of concomitant antiseizure medications.

This study was undertaken to determine the plasma concentration and pharmacokinetic variability of fenfluramine (FFA) and its main active metabolite norfenfluramine (norFFA) in relation to the prevalence of adverse effects in patients with refractory epilepsy treated with FFA. In addition, the interaction with concomitant antiseizure medications including stiripentol (STP) is studied. Patients were recruited at our center from two open-label sources, an investigator-initiated observational study and an international multicenter extension study. Venous blood samples were collected between June 2015 and December 2020. Plasma FFA and norFFA concentrations were determined by liquid chromatography tandem spectrometric analysis. Clinical data were collected retrospectively. Intrapatient coefficient of variation was calculated for all patients with at least three samples. Interpatient variability was calculated based on the concentration to weight-adjusted dose ratio (C/D) of all patients. We collected 321 samples from 61 patients (49 with Dravet syndrome, seven with Lennox-Gastaut syndrome, and five with a developmental and epileptic encephalopathy). With a mean daily dose of .33mg/kg/day (SD =±.16), the median FFA plasma concentration was 41.4µg/L (range = 5.1-712.5) and median norFFA concentration 28.1µg/L (range = 2.6-149.6). The FFA plasma concentration was linearly related to the daily dose (p<.001) and norFFA levels (p<.001). The C/D of FFA increased with age (p<.001). Median FFA C/D was 428% higher (p<.001), norFFA C/D 83% lower (p<.001), and norFFA/FFA 23% lower (p<.001) in patients treated with STP comedication. Higher FFA concentration was associated with fatigue (p=.001) and somnolence (p<.001), but not anorexia (p=.0619) or reduction in seizure frequency (p=.772). Gender and other ASMs were not associated with significant variations in (nor)FFA C/D ratio. Most FFA levels are in the lower range (<50µg/L), although a high interpatient and intrapatient variability is present. In combination with STP, the dose of FFA should be reduced.

Factors in Variability of Serial Gabapentin Concentrations in Elderly Patients with Epilepsy.

To characterize and quantify the variability of serial gabapentin concentrations in elderly patients with epilepsy. This study included 83 patients (age ≥ 60 yrs) from an 18-center randomized double-blind double-dummy parallel study from the Veterans Affairs Cooperative 428 Study. All patients were taking 1500 mg/day gabapentin. Within-person coefficient of variation (CV) in gabapentin concentrations, measured weekly to bimonthly for up to 52 weeks, then quarterly, was computed. Impact of patient characteristics on gabapentin concentrations (linear mixed model) and CV (linear regression) were estimated. A total of 482 gabapentin concentration measurements were available for analysis. Gabapentin concentrations and intrapatient CVs ranged from 0.5 to 22.6 μg/ml (mean 7.9 μg/ml, standard deviation [SD] 4.1 μg/ml) and 2% to 79% (mean 27.9%, SD 15.3%), respectively, across all visits. Intrapatient CV was higher by 7.3% for those with a body mass index of ≥ 30 kg/m2 (coefficient = 7.3, p=0.04). CVs were on average 0.5% higher for each 1-unit higher CV in creatinine clearance (coefficient = 0.5, p=0.03) and 1.2% higher for each 1-hour longer mean time after dose (coefficient = 1.2, p=0.04). Substantial intrapatient variability in serial gabapentin concentration was noted in elderly patients with epilepsy. Creatinine clearance, time of sampling relative to dose, and obesity were found to be positively associated with variability.

Arterial input function and gray matter cerebral blood volume measurements in children.

PurposeTo investigate how arterial input functions (AIFs) vary with age in children and compare the use of individual and population AIFs for calculating gray matter CBV values. Quantitative measures of cerebral blood volume (CBV) using dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) require measurement of an AIF. AIFs are affected by numerous factors including patient age. Few data presenting AIFs in the pediatric population exists.Materials and MethodsTwenty‐two previously treated pediatric brain tumor patients (mean age, 6.3 years; range, 2.0–15.3 years) underwent DSC‐MRI scans on a 3T MRI scanner over 36 visits. AIFs were measured in the middle cerebral artery. A functional form of an adult population AIF was fitted to each AIF to obtain parameters reflecting AIF shape. The relationship between parameters and age was assessed. Correlations between gray matter CBV values calculated using the resulting population and individual patient AIFs were explored.ResultsThere was a large variation in individual patient AIFs but correlations between AIF shape and age were observed. The center (r = 0.596, P < 0.001) and width of the first‐pass peak (r = 0.441, P = 0.007) were found to correlate significantly with age. Intrapatient coefficients of variation were significantly lower than interpatient values for all parameters (P < 0.001). Differences in CBV values calculated with an overall population and age‐specific population AIF compared to those calculated with individual AIFs were 31.3% and 31.0%, respectively.ConclusionParameters describing AIF shape correlate with patient age in line with expected changes in cardiac output. In pediatric DSC‐MRI studies individual patient AIFs are recommended. J. Magn. Reson. Imaging 2016;43:981–989

The Glycemic Indices in Dialysis Evaluation (GIDE) study: Comparative measures of glycemic control in diabetic dialysis patients.

The validity of hemoglobin A1c (HgbA1c) is undergoing increasing scrutiny in the advanced CKD/ESRD (chronic kidney disease/end-stage renal disease) population, where it appears to be discordant from other glycemic indices. In the Glycemic Indices in Dialysis Evaluation (GIDE) Study, we sought to assess correlation of HgbA1c with casual glucose, glycated albumin, and serum fructosamine in a large group of diabetic patients on dialysis. From 26 dialysis facilities in the United States, 1758 diabetic patients (hemodialysis = 1476, peritoneal dialysis = 282) were enrolled in the first quarter of 2013. The distributions of HgbA1c and the other glycemic indices were analyzed. Intra-patient coefficients of variation and correlations among the four glycemic indices were determined. Patients with low HgbA1c values were both on higher erythropoietin (ESA) doses and more anemic. Serum glucose exhibited the highest intra-patient variability over a 3-month period; variability was modest among the other glycemic indices, and least with HgbA1c. Statistical analyses inclusive of all glycemic markers indicated modest to strong correlations. HgbA1c was more likely to be in the target range than glycated albumin or serum fructosamine, suggesting factors which may or may not be directly related to glycemic control, including anemia, ESA management, and iron administration, in interpreting HgbA1c values. These initial results from the GIDE Study clarify laboratory correlations among glycemic indices and add to concerns about reliance on HgbA1c in patients with diabetes and advanced kidney disease.

Lower Variability in 24-Hour Exposure During Once-Daily Compared to Twice-Daily Tacrolimus Formulation in Kidney Transplantation

Tacrolimus has originally been registered as a twice-daily formulation (Prograf, Tac BID), although a once-daily formulation (Advagraf, Tac QD) is also available. A reduced intrapatient variability of Tac Cmin, a surrogate marker for 24-hour drug exposure (AUC0-24), has been suggested. The variability of AUC0-24 has never been studied prospectively yet. The purpose of this study was to investigate the change in intrapatient variability of Tac AUC0-24 after converting from Tac BID to Tac QD. Forty renal transplant patients on Tac BID were converted on a 1:1 (mg/mg) basis to Tac QD in an investigator-driven comparative pharmacokinetic (PK) study. AUC0-24 was determined five times before and after conversion. Duplicate samples were collected by the patients themselves using the dried blood spot method. The main outcome measure is the change in intrapatient variability of AUC0-24 expressed as coefficient of variation (CV). Moreover, the influence of Cyp3A5 genotype polymorphism on the change in CV was studied. In total, 400 AUC0-24 profiles were available for analysis. Conversion to Tac QD resulted in a significant improvement in intra-patient CV from 14.1% to 10.9% (P=0.012). Patients with the Cyp3A5*1/*3 genotype (n=11) had a numerically larger improvement in CV than patients with the CYP3A5*3/*3 genotype. Intrapatient CV of Tac AUC0-24 improved after converting from Tac BID to Tac QD in stable renal transplant patients, especially in patients with the CYP3A5*1/3 genotype. Given the very strict protocol of this PK study, this improvement is most likely due to the different intrinsic PK properties of Tac QD and Tac BID.

Abstract W P158: Permeability as a Biomarker of Cavernous Malformations

Introduction: Vascular hyperpermeability in lesions and nonlesional brain is a cardinal feature of cerebral cavernous malformation (CCM) pathogenesis. Thus we implemented a novel magnetic resonance imaging (MRI) technique in order to quantitate vascular permeability in CCMs and non-CCM brain tissue in humans. We hypothesize that permeability of lesions and background brain will differ between familial and sporadic patients and measurements will be consistent between observers and over time. Method: We used a T 1 -weighted dynamic contrast-enhanced quantitative perfusion (DCEQP) protocol in 30 patients (13 sporadic, 12 familial, and 5 non-CCM cases) in conjunction with routine MRI scans. Regions of interest (ROIs) for permeability measurement included the entire lesion and areas of 12.9 mm 2 (16 pixels) of grey and white matter near and far from the lesion. Measurements were repeated by two observers and at two time points on a subset of patients. Results: For each ROI category except white matter near lesions, the mean permeability was higher in the familial than in the sporadic patients with p-values of 0.04, 0.005, 0.05, and 0.007 for CCM lesions, grey matter near, grey matter far (GMF), and white matter far (WMF) from lesions respectively. No difference was seen between sporadic and non-CCM cases, however familial WMF had higher permeability than both those groups (p0.05) except GMF with p=0.04. The intrapatient coefficients of variation between measurements were 0.74 and 0.63 and interpatient coefficients of variation were 1.36 and 1.56 for sporadic and familial cases respectively. Lastly, it was found that 3 of 4 patients with two scans had stable background (WMF) brain permeability over time. Conclusion: Results show the higher lesional and background brain permeability of familial cases, corroborating previous findings in mice. We also demonstrate the feasibility of DCEQP in CCM disease and the potential of permeability as a biomarker of disease activity or response to treatment. It also highlights the need for further investigation into clinical factors that may impact disease activity and permeability measures.

High variability in baseline urinary free cortisol values in patients with Cushing's disease

ObjectiveTwenty-four-hour urinary free cortisol (UFC) sampling is commonly used to evaluate Cushing’s syndrome. Because there are few data on UFC variability in patients with active Cushing’s disease, we analysed baseline UFC in a large patient cohort with moderate-to-severe Cushing’s disease and assessed whether variability correlates with hypercortisolism severity. These data will help clinicians establish the minimum number of UFC samples required to obtain reliable data.DesignObservational study (enrolment phase of Phase III study).MethodsPatients (n = 152) with persistent/recurrent or de novo Cushing’s disease and mean UFC (mUFC) ≥1·5×ULN (normal: 30–145 nmol/24 h) were included. Mean UFC level was calculated from four 24-h urine samples collected over 2 weeks.ResultsOver 600 24-h UFC samples were analysed. The mUFC levels of samples 1 and 2 and samples 3 and 4 were 1000 nmol/24 h (SD 1872) and 940 nmol/24 h (SD 2148), respectively; intrapatient coefficient of variation (CV) was 38% for mUFC. The intrapatient CV using all four samples was 52% (95% CI: 48–56). The intrapatient CV was 51% (95% CI: 44–58) for samples 1 and 2, 49% (95% CI: 43–56) for samples 3 and 4 and 54% (95% CI: 49–59) for samples 1, 2 and 3. Variability in mUFC increased as UFC levels increased. There were no correlations between UFC and clinical features of hypercortisolism.ConclusionsThere is intrapatient variability of approximately 50% in 24-h UFC measurements, which is relevant to targets set to estimate any treatment effect. Analysing more than two 24-h collection periods in individual patients does not result in a relevant decrease in variability. Interestingly, UFC levels did not correlate with hypercortisolism severity.

Optimizing the Use of a Skin Prick Test Device on Children

Background: Studies comparing skin prick test (SPT) devices have revealed varying results in performance and there is little known about their use on children. Methods: We performed 2 complementary studies to test the sensitivity, reproducibility and acceptability of commercially available SPT devices (Stallerpoint, Antony, France) using different application techniques. In the first part, histamine/saline was put on as a drop by use of a vial (V), and in the second part it was transferred from a well with the aid of the test device (W). The techniques were as follows: apply vertical pressure (Stallerpoint-VP or Stallerpoint-WP), apply vertical pressure with 90° clockwise rotation (Stallerpoint-VC or Stallerpoint-WC) and apply vertical pressure with 90° clockwise and counter-clockwise rotations (Stallerpoint-VCC or Stallerpoint-WCC). For comparison, ALK Lancet was used with a technique of ‘drop and apply vertical pressure'. Results: In the first part, sensitivities of the Stallerpoint-VC (96.6%), Stallerpoint-VCC (95.5%) and ALK Lancet (93.2%) techniques were superior (p < 0.001) to the other Stallerpoint-VP and Stallerpoint-WP techniques (76.1 and 46.6%). Intrapatient coefficient of variation (CV) values were 15.0, 18.9, 15.4, 22.4 and 48.5%, respectively. Interpatient CV ranged between 22.8 and 55.1%. In the second part, the Stallerpoint-WC (98.8%), WCC (97.5%) and ALK Lancet (98.8%) techniques yielded high sensitivities, whereas the sensitivity of Stallerpoint-WP (28.7%) was very low. There were false-positive reactions in the Stallerpoint-VCC and WCC techniques. Conclusion: In children, the SPT technique was found to be as important as the testing device. Stallerpoint-VC and WC techniques are reliable, tolerable and comparable with the ALK Lancet technique.

Performances of an Improved Device for Skin Prick Tests

Every day allergists deal with skin prick testing. Following a recent paper showing that the intravenous needle and the metal lancets are superior to the Stallerpoint® plastic lancet, the manufacturer has improved the device to reach better standards in terms of sensitivity, intra-patient reproducibility and inter-patient reproducibility, as demonstrated on 10 adult patients, comparing the results with skin tests performed with the intravenous needle. We evaluated the sensitivity of the device by calculating the ratio between the number of true-positive tests and the sum of true-positive and false-negative tests. To assess the reproducibility of the test, we calculated the interpatient and the intrapatient coefficient of variation between the mean diameters of the papules induced by the different techniques. The improved device shows performances similar to those obtained with the intravenous needle.

Impact of Variability of Sirolimus Trough Level on Chronic Allograft Nephropathy

The efficacy of sirolimus is strictly dose-dependent; an inappropriate exposure may cause either rejection episodes or drug toxicity. The variability of sirolimus trough levels (C 0) may also have an impact on renal allograft function. We prospectively evaluated the impact of the dose-normalized C 0 of sirolimus and the intrapatient coefficient of variation (% CV) on renal allograft function at 6 months after the administration of sirolimus to kidney transplant recipients with chronic allograft nephropathy (CAN). We enrolled 51 recipients with CAN who were treated with sirolimus. The dose-normalized C 0 of sirolimus was 3.8 ± 1.9 ng/mL/mg. The intra- and interpatient variabilities of sirolimus C 0 were 26.1% and 51.9%, respectively. Based on receiver operating characteristic analysis, patients were divided into 2 groups: group I, sirolimus % CV <22.9% (n = 36) versus group II, sirolimus % CV >22.9% (n = 15). Patients in group II experienced significantly greater risk for progressive deterioration of allograft function (group I vs group II: 11.1% vs 73.3%; P < .05). Multiple logistic regression analysis revealed that higher baseline serum creatinine, but not age, gender, or concomitant immunosuppressants, positively correlated with the sirolimus % CV. In conclusion, both higher baseline serum creatinine and higher intraindividual variability of sirolimus C 0 impact the outcome of renal allograft function in CAN. Thus, we suggest that close monitoring of sirolimus C 0 is necessary for recipients treated with sirolimus, especially for patients with CAN.

Reproducibility of plasma insulin kinetics during intraperitoneal insulin treatment by programmable pumps

To study the reproducibility of plasma insulin kinetics during intraperitoneal (IP) insulin therapy using an implanted programmable pump in patients with type 1, insulin dependent, diabetes mellitus (IDDM). In a group of ten type 1 IDDM patients beginning chronic IP insulin treatment with an implanted pump, plasma free insulin profiles were determined from 12: 00 am to 12: 30 pm on two separate test days, one month apart. Anti-insulin antibody (AIA) levels were measured on each test day. From test day 1 to test day 2, no difference was observed in morning fasting free insulin levels (m +/- SD): 9.7 +/- 5.4 mU/L versus 9.8 +/- 5.3 mU/L, insulin peak values: 19.1 +/- 17 mU/L versus 20.8 +/- 9.9 mU/L, time to peak: 40 +/- 15 versus 42.8 +/- 16 minutes or post-bolus area under the plasma free insulin curve (AUC): 40.7 +/- 29 mU/L.h versus 45.5 +/- 29 mU/L.h. The intrapatient coefficient of variation was 14.4 +/- 13% for insulin peaks and 16.9 +/- 9.2% for post-bolus AUC. A significant increase in AIA levels (m +/- SD) was observed from 16.5 +/- 18% on test day 1 to 28.1 +/- 28% on test day 2. The reproducibility of plasma free insulin profiles is highly satisfactory during insulin delivery by the IP route using an implanted device.

Serum FSH levels in women with polycystic ovary syndrome during ovulation induction using down-regulation and urofollitropin.

To evaluate retrospectively the use of serum FSH levels and to correlate them with follicular growth in a clinical ovulation induction program. Twenty women with infertility due to anovulation associated with polycystic ovary syndrome (PCOS) were studied. The patients were down-regulated with a long GnRH agonist protocol and stimulated with purified urofollitropin, using a low-dose step-up regimen. Repeated serum samples were drawn and transvaginal ultrasound scans were-performed. During the exogenous FSH therapy serum FSH levels resulting in continuous follicular growth were analyzed, as well as the rates of ovulation, pregnancy, cancellation and conversion to in vitro fertilization (JVF). Thirty-two out of fifty treatment cycles led to ovulation, resulting in five term pregnancies. Eight cycles were converted to IVF/embryo transfer due to multiple follicular growth. They resulted in two pregnancies. Ten cycles were cancelled because of impaired follicular growth. The serum FSH levels (median 6 IU/I) resulting in continuous growth of the follicles were relatively stable within patients (variation 15%) but varied considerably between patients (45%). The relationship between FSH dose and serum level was different for lean and obese PCOS patients after subcutaneously injected urofollitropin There seems to be a difference in resorption/metabolism between lean and obese PCOS patients with regard to s.c. injected FSH. The intra-patient coefficient of variation (C.V.) of the serum FSH response level was quite low, as was the C.V. of the FSH dose at the response level. This allowed a more rapid dose adjustment in subsequent cycles. Analysis of serum FSH during induction of ovulation with gonadotropins seems to be of limited value in clinical programs.

The Assessment and Clinical Implications of Haloperidol Acute-Dose, Steady-State, and Withdrawal Pharmacokinetics

In order to evaluate comprehensively haloperidol pharmacokinetics under fixed-dose treatment conditions, psychiatric patients were studied after treatment with an acute dose, during maintenance therapy, and after withdrawal from haloperidol following steady-state conditions. After single doses, haloperidol appeared rapidly in serum, achieving peak concentration at a mean of 4.5 hours. The range of observed elimination half-life was broad, between 8.5 and 66.6 hours, with a mean of 19.5 hours. Under conditions of chronic dosing, serial measurements of steady-state serum concentration revealed intrapatient coefficients of variation between 2 and 72%. The mean for all patients was 26.4%. Body clearance decreased nonsignificantly, and elimination half-life increased significantly after chronic dosing compared with kinetic parameters determined after a single dose. The concentration of haloperidol in serum obtained at 8 hours after a single dose correlated most strongly (r = 0.73; p < 0.0001) with steady-state concentration resulting from chronic dosing. A value of 4 ng/ml or lower determined 8 hours after a single oral dose of 0.2 mg/kg identified patients who did not accumulate haloperidol during chronic dosing of 0.4 mg/kg per day above a presumed therapeutic range for haloperidol of 5 to 15 ng/ml. The implications of these data for the clinical use of haloperidol are discussed.

Pharmacokinetics of quinidine in male patients. A population analysis.

Quinidine pharmacokinetic behaviour was evaluated in 139 adult hospitalised men receiving oral quinidine therapy. A total of 391 serum quinidine concentrations were measured by enzyme immunoassay for routine clinical purposes. The NONMEM programme was used to examine the relationship between quinidine pharmacokinetics and several potential covariates. A 1-compartment open model with first-order absorption and elimination was assumed. The mean apparent volume of distribution (Vd) was about 230L. When measured, alpha 1-acid glycoprotein (AAG) levels were not included in the analysis. Oral quinidine clearance (CL) decreased with age, severe congestive heart failure and renal disease, and increased in patients with a history of alcohol abuse. The interpatient variability in CL and the intrapatient residual variability expressed as coefficients of variation (CV) were 28 and 31%, respectively. When AAG values were incorporated into the analysis, the only important covariates of CL were the AAG measurements and the presence of renal dysfunction as indicated by a calculated creatinine clearance of less than 50 ml/min (3 L/h). The interpatient variability in CL and the residual intrapatient CVs decreased to approximately 24 and 26%, respectively. Improvement of the CL model by inclusion of measured AAG strongly suggests that quinidine elimination is dependent on the free concentration of drug in plasma and supports the use of free serum quinidine concentrations when evaluating and monitoring quinidine therapy.

Variability and reproducibility in the measurement of tracheobronchial clearance in healthy subjects and patients with different obstructive lung diseases

The purpose of this study was to establish the inter- and intra-subject/patient variability of tracheobronchial clearance, measured for 6 h, using a radioaerosol technique. Inter-subject variability was evaluated in five groups: 33 healthy non-smokers (NS); 19 asymptomatic smokers (S); 40 asthmatics (A); 27 chronic bronchitics (CB) and 12 bronchiectatics (B). Intra-subject variability was evaluated in 16 A and 27 CB who were studied twice. The inter-subject/patient coefficient of variation (CoV) of tracheobronchial clearance was 13% for NS and 28-39% for the remaining four groups. The intra-patient CoV was about half of the inter-patient CoV. Inter-subject CoV (for A and CB) appeared to be independent of initial tracheobronchial deposition of radioaerosol and frequency of cough. We were also able to estimate the approximate number of patients required for a crossover study in order to avoid statistical, type II errors when investigating the effect of a drug or of a therapeutic intervention on tracheobronchial clearance.